You Make the Call
Each month in “ You Make the Call ,” we ’ ll pick a challenging clinical question submitted through ASH ’ s Consult a Colleague program and post the expert ’ s response , but we also want to know what you would do . Send in your responses to next month ’ s clinical dilemma and see how your answer matches up to the experts ’ in the next print issue .
This month , Margaret V . Ragni , MD , MPH , discusses treatment options for a pregnant patient with type 2A von Willebrand disease .
TRAINING and EDUCATION
Clinical Dilemma :
I have a patient at 37 weeks of her fourth pregnancy . She has a history of type 2A von Willebrand disease ( vWD ), requiring Humate-P replacement in the prior two deliveries and other bleeding occasions ( epistaxis , hematuria , and heavy menses prior to last pregnancy , which required monthly doses of Humate-P 1,450 units ). She will undergo vaginal induction delivery in two weeks . She weighs 161 pounds . Her current values are as follows : PT , PTT , and fibrinogen are normal ; factor VIII ( FVIII ) is 96 percent ; von Willebrand factor ( vWF ) antigen is 113 percent ; and vWF activity is 34 percent . My recommendations include keeping activity level at 100 percent prior to delivery and three days postpartum , Humate-P 2,400 units 30 minutes prior to epidural , then the same dose every 12 hours for three days followed by Humate-P 1,450 units daily until hemostasis is achieved . Are my dosing recommendations correct ?
Expert Opinion
Margaret V . Ragni , MD , MPH Professor of Medicine and Clinical Translational Science Department of Medicine University of Pittsburgh Medical Center Pittsburgh , Pennsylvania
Your question is important , as few guidelines exist that address managing delivery in women with vWD , and the guidelines that do exist are grade III , level C ( expert opinion ). 1-3 It is recommended that vWF 50 IU / kg should be given pre-delivery / epidural followed by up to three days postpartum . The problem is that , despite treatment , women with vWD have a 1.4-fold greater blood loss and 1.4-fold lower vWF levels than those without . 4 Why treatment fails and what the optimal treatment is for women with vWD at delivery is not known ; however , it is the subject of a planned randomized controlled trial ( PREVENT PPH ). 5
In normal pregnancy , blood volume increases , peaking by 1.5-fold by the third trimester . 6-8 At the same time , vWF levels progressively increase , peaking at delivery and falling to pre-pregnancy levels within three weeks . Yet , guidelines suggest vWF 50 IU / kg only for those with third trimester vWF levels < 0.50 IU / mL , noticeably lower than the 80 IU / kg dose for general surgery . 1-3 The failure of 50 IU / kg to prevent postpartum bleeding suggests more effective treatment is needed . vWF treatment is suggested for women with thirdtrimester vWF : RCo levels < 0.50 IU / dL . Yet , the basis for this recommendation is unclear . In a recent retrospective study of women with vWD , factors associated with postpartum bleeding (> 500 mL ) included low pre-pregnancy vWF , a high pre-pregnancy bleeding score ( ≥5 ), high pre-pregnancy weight , and a family history of bleeding . 4 Although this was a small single-center study , it suggests pre-pregnancy disease severity is important in assessing postpartum bleeding risk .
The vWF dose recommended at delivery is 50 IU / kg . Delivery is a surgical procedure , and the basis for using a dose lower than what is used for general surgery is unclear . It is known that some experts avoid vWF doses above 50 IU / kg in pregnant women because of the increased risk of thrombosis associated with the gravid state . A literature review of 13 studies from 1992 to 2015 of 474 non-pregnant patients with vWD treated with up to vWF 220 IU / kg , the thrombosis rate was low at 0.4 percent . 5 These data suggest the risk of thrombosis in pregnancy also may be low . The question of whether vWF dosing should be based on body weight or blood volume , which increases 1.4-fold during pregnancy will requires further study . 6-8
Compared with plasma-derived vWF , recombinant vWF has no infectious agent transmission , prolongs
half-life 1.4-fold , and has greater purity and potency promoting platelet and collagen binding and FVIII stabilization , with no increased risk of thrombosis , as it is degraded by patient ’ s own ADAMTS-13 . 9 , 10 Its longer half-life may potentially reduce dose frequency , compared with plasma-derived vWF .
Based on the above considerations , it would be reasonable to use plasma-derived vWF 50 to 80 IU / kg or recombinant vWF 50 to 80 IU / kg just prior to epidural or spinal anesthesia , or delivery , and for the first three to five days postpartum . Additional dosing would be indicated for continued or uncontrolled bleeding , which can last up to six weeks postpartum in women with vWD .
REFERENCES
1 . Nichols WL , Hultin MB , James AH , et al . von Willebrand disease ( VWD ): evidence-based diagnosis and management guidelines , the National Heart , Lung , and Blood Institute Expert Panel report ( USA ). Haemophilia . 2008 ; 14:171-232 .
2 . National Hemophilia Foundation . MASAC guidelines for perinatal management of women with bleeding disorders and carriers of hemophilia A and B . Medical and Scientific Advisory Committee , document # 192 . New York , 2009 .
3 . Laffan MA , Lester W , O ’ Donnell JS , et al . The diagnosis and management of von Willebrand disease : a United Kingdom Haemophilia Centre Doctors Organization guideline approved by the British Committee for Standards in Haematology . Br J Haematol . 2014 ; 167:453-65 .
4 . James AH , Konkle BA , Koudies P , et al . Postpartum von Willebrand factor levels in women with without von Willebrand disease and implications for prophylaxis . Haemophilia . 2015 ; 21:81-7 .
5 . Ragni MV , Machin N , Seaman CD , et al . Feasibility of the Von Willebrand disease PREVENT trial . Thromb Res . 2017 ; 156:8-13 .
6 . Hytten F . Blood volume changes in normal pregnancy . Clin Hematol . 1985 ; 14:601-12 .
7 . Clark SL , Cotton DB , Lee W , et al . Central hemodynamic assessment in normal term pregnancy . Am J Obstet Gynecol . 1989 ; 161:1439-42 .
8 . Liu LX , Arany Z . Maternal cardiac metabolism in pregnancy . Cardiovas Res . 2014 ; 101:545-53 .
9 . Gill J , Castaman G , Windyga J , et al . Safety , efficacy , pharmacokinetics of recombinant VWF in patients with severe von Willebranddisease . Blood . 2015 ; 126:2038-46 .
10 . Turecek PL , Schrenk G , Rottensteiner H , et al . Structure and function of a recombinant von Willebrand factor drug candidate . Semin Thromb Hemost . 2010 ; 36:510-21 .
Next Month ’ s Clinical Dilemma :
A 33-year-old transgender female patient was involved in a motor vehicle accident that resulted in several injuries and required a 91-day hospitalization . At the time of the accident , she was on hormone replacement therapy ( HRT ), which was stopped during her stay in the intensive care unit . About 26 days into her hospitalization , she had a deep vein thrombosis and pulmonary embolism . She had an inferior vena cava filter placed and was started on anticoagulation . Will she be able to go back on HRT ? She had been on HRT for eight years with no problems and has no family history of thromboembolic disease .
Visit ashclinicalnews . org / you-make-the-call to read the full dilemma and send in your response . ●
Consult a Colleague Through ASH
Consult a Colleague is a service for ASH members that helps facilitate the exchange of information between hematologists and their peers . ASH members can seek consultation on clinical cases from qualified experts in 11 categories :
• Anemias
• Hematopoietic cell transplantation
• Hemoglobinopathies
• Hemostasis / thrombosis
• Lymphomas
• Lymphoproliferative disorders
• Leukemias
• Multiple myeloma & Waldenström macroglobulinemia
• Myeloproliferative disorders
• Myelodysplastic syndromes
• Thrombocytopenias
Assigned volunteers (“ colleagues ”) will respond to inquiries within two business days ( either by email or phone ).
Have a puzzling clinical dilemma ? Submit a question , and read more about Consult a Colleague volunteers at hematology . org / Clinicians / Consult . aspx or scan the QR code .
* If you have a request related to a hematologic disorder not listed here , please email your recommendation to ashconsult @ hematology . org so it can be considered for addition in the future .
DISCLAIMER : ASH does not recommend or endorse any specific tests , physicians , products , procedures , or opinions , and disclaims any representation , warranty , or guaranty as to the same . Reliance on any information provided in this article is solely at your own risk .
64 ASH Clinical News January 2018